1. Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications.
- Author
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Guiastrennec, Benjamin, Ramachandran, Geetha, Karlsson, Mats O, Kumar, AK Hemanth, Bhavani, Perumal Kannabiran, Gangadevi, N Poorana, Swaminathan, Soumya, Gupta, Amita, Dooley, Kelly E, and Savic, Radojka M
- Subjects
Humans ,Tuberculosis ,HIV Infections ,Body Weight ,Isoniazid ,Pyrazinamide ,Rifampin ,Antitubercular Agents ,Drug Monitoring ,Treatment Outcome ,Drug Therapy ,Combination ,Drug Administration Schedule ,Age Factors ,Dose-Response Relationship ,Drug ,Models ,Biological ,Time Factors ,Adolescent ,Child ,Child ,Preschool ,Infant ,India ,Female ,Male ,Drug Dosage Calculations ,Coinfection ,Drug Therapy ,Combination ,Dose-Response Relationship ,Drug ,Models ,Biological ,Preschool ,Pharmacology and Pharmaceutical Sciences ,Pharmacology & Pharmacy - Abstract
This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (Punfavorable ). Model-based simulation of optimized (Punfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines.
- Published
- 2018